Pulmonary failure, from smoke inhalation, remains a leading cause of mortality and morbidity in the burn patient. Mucosal edema, ulcerations and slough leading to a denuded severely altered airway lining occurs in the 24-36 hrs. following exposure. Distal atelectasis is also evident as is airways exudate and fluid. We have now demonstrated lung airways and systemic oxidant changes after smoke inhalation, initiated most likely by the particles in smoke. The degree of lung oxidant activity measured as lipid peroxides, corresponds with the severity of airways damage and atelectasis. The smoke injury also causes systemic oxidant activity and major physiologic changes especially when a skin burn is also present. Currently, the only treatment for smoke inhalation with or without a burn is supportive therapy to clear the bronchorrhea and mucosal fragments and ventilator management to maintain gas exchange. Our published and preliminary data indicate oxidants are the primary agent, initiating the injury and antioxidants can block the injury process. Our specific aims are first to further define the mechanism of the initial mucosal injury comparing more precise anatomic changes with physiologic and biochemical changes over the initial 24 hour time course. We want to determine the smoke particle deposition in the lung relative to the anatomic injury, using fluorescent and radiolabelling. We then want to determine the mechanism of the increased oxidant activity in the lung and systemically, in particular the relationship of proinflammatory cytokines and free iron. We also want to determine the response of key antioxidants given, especially by aerosol, early in the course of injury. Second, we want to determine the mechanism by which a body burn affects the lung injury and vice versa. Why does a burn prolong the smoke inhalation injury. Thirdly, we want to determine the interrelationship between the lung and the systemic response. Are the mediators released from the lung responsible? A very reproducible sheep and rat smoke model will be used. Our long-term objectives are to develop antioxidant therapies that can prevent the initial smoke induced injury process from evolving to lung dysfunction.